Antigen-Specific Therapeutic Approaches in Type 1 Diabetes

Abstract

Development of strategies capable of specifically curbing pathogenic autoimmune responses in a disease-and organ-specific manner without impairing foreign or tumor antigen-specific immune responses represents a long sought-after goal in autoimmune disease research. Unfortunately, our current understanding of the intricate details of the different autoimmune diseases that affect mankind, including type 1 diabetes, is rudimentary. As a result, progress in the development of the so-called "antigen-specific" therapies for autoimmunity has been slow and fraught with limitations that interfere with bench-tobedside translation. Absent or incomplete understanding of mechanisms of action and lack of adequate immunological biomarkers, for example, preclude the rational design of effective drug development programs. Here, we provide an overview of antigen-specific approaches that have been tested in preclinical models of T1D and, in some cases, human subjects. The evidence suggests that effective translation of these approaches through clinical trials and into patients will continue to meet with failure unless detailed mechanisms of action at the level of the organism are defined.C urrent approaches toward a potential cure for Type I diabetes (T1D) have focused on three main targets: (1) ablation of the b-cell-specific autoimmune response; (2) b-cell replacement therapy using islet transplantation; and (3) potentiation of b-cell mass and function using pharmacologic agents capable of promoting b-cell proliferation, regeneration and/or repair.Pancreasandislet-transplantationin thecontext of systemic immunosuppression are the only approaches that have afforded patients complete independence from exogenous insulin. However, they have also highlighted the fact that, in the absence of immunosuppression, transplantation invariably meets with failure. For example, although 70% of islet-grafted patients remain insulin independent 1 year after transplantation, a significant fraction of them revert to insulindependency within 5 years, albeit with significantly lower insulin needs (Shapiro et al. 2000Merani and Shapiro 2006;Robertson 2010). Because disease recurrence is typically associated with an anamnestic autoimmune response against the grafted tissue (Laughlin et al.

Are Obesity-Related Insulin Resistance and Type 2 Diabetes Autoimmune Diseases?

“…These therapies might replace or complement existing approaches aimed at targeting inflammatory pathways, such as with salicylates and cytokine-neutralizing biologics (72,73), though the implementation of these novel approaches would have to be carefully balanced by proper risk assessment of immunodeficiency-related side effects. In addition, as autoimmunity implies antigen specificity, self-antigen-specific immune responses might be curbed one day by better tolerated antigen-specific immunotherapies, with approaches that overcome current technical obstacles associated with the development of antigen-specific immunotherapy in humans (8). Advances that shed light on the relationship between gut microbiome and gut-associated immune pathways in obesity have opened up yet another avenue of therapeutic strategies -improving insulin resistance through the manipulation of diet, gut biodiversity, and potentially the gut immune pathways.…”

“…Loss of tolerance toward self is supported by ample evidence pointing toward defective immune regulation, manifested as a result of combined environmental and predisposing genetic factors (4,7). Furthermore, researchers have devised immunotherapeutic strategies based on these findings, many of which are being tested clinically as potential treatment for these autoimmune diseases (8).…”

Optimal T-cell receptor affinity for inducing autoimmunity

“…Similar findings have been reported for the rat insulin promoter (RIP)-membrane-bound form of ovalbumin (mOVA) mouse line coexpressing the OT-I TCR (OVA transgenic-I T-cell receptor) β-chain (17). Self-reactive T cells also play a role in the spontaneous development of diabetes in nonobese diabetic (NOD) mice (19).…”

Antigen-Specific Immune Modulation Targets mTORC1 Function To Drive Chemokine Receptor–Mediated T Cell Tolerance

“…Ag-induced tolerance specifically targets pathogenic T cells while circumventing generalized immune suppression (3, 36). Mechanisms that tend to physiological peripheral tolerance, including interference with activating costimulation (9), induction of costimulation inhibitory molecules (37), and expansion of T regulatory cells (11, 12) constitute the major ingredients for Ag-specific tolerance.…”